The present invention relates to the field of targeted drug delivery.
The efficacy of a drug may be improved by altering its biodistribution such that the drug is localized at the site of disease. The advantages include, for example, improved activity in the treatment or prevention of disease and, in some instances, reduced toxicity.
One general approach to altering biodistribution involves changing the formulation of a drug. For example, in a nanoparticulate formulation (e.g., liposome, biodegradable polymer, or solid lipid nanoparticle), a drug is directed to organs and tissues of the RES system (e.g., liver, spleen, lung, vascular macrophage). Alternatively, a drug's biodistribution can be altered by covalently linking it to a targeting moiety, e.g., a ligand for an endogenous receptor or a molecule that facilitates transport into cells and/or tissues. Examples of ligands for endogenous receptors include biotin, antibodies, and receptor-targeted peptides (e.g., RGD peptides and somatostatin). Examples of targeting moieties that can facilitate transport include small proteins and peptides that permeate plasma membranes (e.g., HIV-1 tat peptide). The biodistribution of the drug incorporated into a targeting moiety-drug conjugate is altered under the influence of the targeting moiety.
The literature describing the bioconjugate techniques involved in the preparation of targeting moiety-drug conjugates is extensive. In some instances, the conjugates are linked by biodegradable linkers, either to aid in the elimination of the drug or to improve the activity of the drug, once it has been delivered to the desired tissue.
Many diseases exist for which there are few effective treatments. For example, the number of drug resistant pathogens is continually increasing. Thus, improved methods are needed for the treatment and prevention of disease. Some of these new methods, as discussed above, focus on mechanisms of delivering drugs to diseased tissues. These include methods which modulate the biodistribution or membrane transport of drugs. Desirably, these new treatments enhance the efficacy of the drug without introducing adverse side-effects.